Fibronectin fragments have both catabolic and anabolic activities toward articular cartilage explants in vitro. Whereas a 1 nM concentration of an N-terminal 29 kDa fibronectin fragment (Fn-f) increases the proteoglycan (PG) content of cartilage without induction of matrix metalloproteinases (MMPs), 0.1Ő1 ƁM Fn-f temporarily suppresses PG synthesis and enhances MMP release. The higher concentrations cause an initially rapid PG depletion during the first week of culture, followed by much slower PG loss and gradually increasing rates of PG synthesis. To test for the involvement of mediators, human articular cartilage was cultured with Fn-f, and conditioned media were assayed for selected cytokines and factors. With 1 nM Fn-f, the release of the anabolic factors, insulin growth factor-I and transforming growth factor β1, from cultured cartilage was enhanced by 50Ő100% during the entire 28-day culture period and this was associated with both supernormal rates of PG synthesis and PG content. However, the higher concentrations of Fn-f additionally enhanced release, by at least 10-fold, of the cytokines, tumour necrosis factor α, interleukin-1α, interleukin-1β and interleukin-6 while causing depletion of cartilage PG. Release of tumour necrosis factor α, interleukin 1β and interleukin 1α peaked at days 2, 3 and 9 during or slightly after the period of maximal PG depletion and decreased to control levels by days 7, 7 and 21 respectively, whereas release of interleukin 6 was enhanced throughout the culture period. Neutralizing antibodies to the catabolic cytokines reduced Fn-f-mediated MMP-3 release and suppression of PG synthesis. The temporal aspects of this interplay between catabolic and anabolic factors are consistent with the kinetics of Fn-f-mediated cartilage damage and attempted repair and may be relevant to cartilage damage and repair in vivo.

These data demonstrate that although Fn-fs could be generated in vivo within synovial fluids and Fn-fs found in OA synovial fluid may contribute to cartilage damage in vivo, Fn-fs could also be generated within cartilage and amplify cartilage damage. Thus, Fn-fs may be both autocrine and paracrine regulators of cartilage metabolism.

Regional perfusion imaging (RPI) has recently been introduced as a potentially powerful technique to map the perfusion territories of patients with vascular diseases in a fully noninvasive manner. However, this technique suffers from the problems of the transfer insensitive labeling technique upon which it is based. In particular, RPI is very sensitive to magnetic field inhomogeneities, and therefore the definition of the labeled bolus can deteriorate at field strength higher than 1.5 T. Furthermore, the slab-selective triple-pulse postsaturation sequence used originally will also be impaired due to the same problem, rendering RPI unusable at higher field. In this work, an adiabaticbased signal targeting with alternating radiofrequency pulses sequence is proposed as a labeling scheme to solve the problems related to variations in local magnetic field, together with an improved four-pulse water suppression enhanced through T 1 effects technique as a presaturation scheme. Magn Reson Med 53: 15-21, 2005.